Role of RAS in the Regulation of PI 3-Kinase

Ras proteins are key regulators of signalling cascades, controlling many processes such as proliferation, differentiation and apoptosis. Mutations in these proteins or in their effectors, activators and regulators are associated with pathological conditions, particularly the development of various forms of human cancer. RAS proteins signal through direct interaction with a number of effector enzymes, one of the best characterized being type I phosphatidylinositol (PI) 3-kinases. Although the ability of RAS to control PI 3-kinase has long been well established in cultured cells, evidence for a role of the interaction of endogenous RAS with PI 3-kinase in normal and malignant cell growth in vivo has only been obtained recently. Mice with mutations in the PI 3-kinase catalytic p110a isoform that block its ability to interact with RAS are highly resistant to endogenous KRAS oncogene induced lung tumourigenesis and HRAS oncogene induced skin carcinogenesis. Cells from these mice show proliferative defects and selective disruption of signalling from certain growth factors to PI 3-kinase, while the mice also display delayed development of the lymphatic vasculature. The interaction of RAS with p110a is thus required in vivo for some normal growth factor signalling and also for RAS-driven tumour formation. RAS family members were among the first oncogenes identified over 40 years ago. In the late 1960s, the rat-derived Harvey and Kirsten murine sarcoma retroviruses were discovered and subsequently shown to promote cancer formation through related oncogenes, termed RAS (from rat sarcoma virus). The central role of RAS proteins in human cancer is highlighted by the large number of tumours in which they are activated by mutation: approximately 20% of human cancers carry a mutation in RAS proteins. Because of the complex signalling network in which RAS operates, with multiple activators and effectors, each with a different pattern of tissue-specific expression and a distinct set of intracellular functions, one of the critical issues concerns the specific role of each effector in RAS-driven oncogenesis. In this chapter, we summarize current knowledge about how RAS regulates one of its best-known effectors, phosphoinositide 3-kinase (PI3K).